Project Summary and Relevance Gene drive systems could solve ecological problems by altering entire populations of wild organisms. However, the self-sustaining nature of current CRISPR-based drive systems makes them likely to spread to most local populations, and very possibly to other populations of that species elsewhere in the world. Without a means of safe testing or securing international agreement prior to deployment, it is unclear how these types of gene drive systems can be ethically released. This proposal seeks to develop ?daisy drive? systems capable of precisely and economically altering local populations of wild organisms. Specifically, the project will develop ways of reducing the fitness cost of both alteration and suppression drive systems, precisely controlling the extent to which they will spread, and perfectly reversing genetic changes spread by other types of CRISPR-based drive systems. By providing a path to community-supported, diplomatically feasible, and economical deployment, this proposal will facilitate the prevention of numerous vector-borne and parasitic diseases by spreading disease resistance among vectors or directly suppressing populations of disease agents. We anticipate that daisy drive interventions will serve as powerful weapons suitable for combating malaria, schistosomiasis, dengue, Zika, Lyme disease, and many more.